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INFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

Selective Inhibition of Plasma Kallikrein Protects Brain from Reperfusion Injury

Department of Neuroscience, Mario Negri Institute, Milan (C.S., R.G., M.G.D.S.); and Geriatric Unit, Ospedale Maggiore, University of Milan, Italy (L.B., E.R., D.M.)

We have studied the effect of DX-88, a selective recombinant inhibitor of human plasma kallikrein, in transient or permanent focal brain ischemia (with or without reperfusion, respectively) induced in C57BL/6 mice. Twenty-four hours after transient ischemia, DX-88 administered at the beginning of ischemia (pre) induced a dose-dependent reduction of ischemic volume that, at the dose of 30 µg/mouse, reached 49% of the volume of saline-treated mice. At the same dose, DX-88 was also able to reduce brain swelling to 32%. Mice treated with DX-88 pre had significantly lower general and focal deficit score. Fluoro-Jade staining, a marker for neuronal degeneration, showed that DX-88-treated mice had a reduction in the number of degenerating cells, compared with saline-treated mice. Seven days after transient ischemia, the DX-88 protective effect was still present. When the inhibitor was injected at the end of ischemia (post), it was still able to reduce ischemic volume, brain swelling, and neurological deficits. DX-88 efficacy was lost when the inhibitor was given 30 min after the beginning of reperfusion (1 h post) or when reperfusion was not present (permanent occlusion model). This study shows that DX-88 has a strong neuroprotective effect in the early phases of brain ischemia preventing reperfusion injury and indicates that inhibition of plasma kallikrein may be a useful tool in the strategy aimed at reducing the detrimental effects linked to reperfusion.

Address correspondence to: Dr. Maria Grazia De Simoni, Laboratory of Inflammation and Nervous System Diseases, Mario Negri Institute, via Eritrea, 62, 20157 Milano, Italy. E-mail: desimoni{at}marionegri.it